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- Title
Overcoming Diabetes-Induced Hyperglycemia through Inhibition of Hepatic Phosphoenolpyruvate Carboxykinase (GTP) with RNAi.
- Authors
Gómez-Valadés, Alicia G.; Vidal-Alabró, Anna; Molas, Maria; Boada, Jordi; Bermúdez, Jordi; Bartrons, Ramon; Perales, José C.
- Abstract
Phosphoenolpyruvate carboxykinase (PEPCK; EC 4.1.1.32) is the rate-controlling enzyme in gluconeogenesis. In diabetic individuals, altered rates of gluconeogenesis are responsible for increased hepatic glucose output and sustained hyperglycemia. Liver-specific inhibition of PEPCK has not been assessed to date as a treatment for diabetes. We have designed a therapeutic, vector-based RNAi approach to induce posttranscriptional gene silencing of hepatic PEPCK using nonviral gene delivery. A transient reduction of PEPCK enzymatic activity (7.6 ± 0.6 vs 9.7 ± 1.1 mU/mg, P < 0.05) that correlated with decreased protein content of up to 50% was achieved using this strategy in diabetic mice. PEPCK partial silencing was sufficient to demonstrate lowered blood glucose (218 ± 26 vs 364 ± 33 mg/dl, P < 0.001) and improved glucose tolerance together with decreased circulating FFA (0.89 ± 0.10 vs 1.44 ± 0.11 mEq/dl, P < 0.001) and TAG (65 ± 11 vs 102 ± 16 mg/dl, P < 0.01), in the absence of liver steatosis or lactic acidosis. SREBP1c was down-regulated in PEPCK-silenced animals, suggesting a role for this pathway in the alterations of lipid metabolism. These data reinforce the significance of PEPCK in sustaining diabetes-induced hyperglycemia and validate liver-specific intervention at the level of PEPCK for diabetes gene therapy.Molecular Therapy (2006) 13, 401–410; doi: 10.1016/j.ymthe.2005.08.026
- Subjects
PYRUVATE kinase; GLUCONEOGENESIS; PEOPLE with diabetes; DIABETES; HYPERGLYCEMIA
- Publication
Molecular Therapy, 2006, Vol 13, Issue 2, p401
- ISSN
1525-0016
- Publication type
Article
- DOI
10.1016/j.ymthe.2005.08.026